Tricyclic compounds

ABSTRACT

Tricyclic compounds of the formula : WHEREIN N IS AN INTEGER FROM 1 TO 11 INCLUSIVE ; R is hydrogen or lower alkyl ; X and Y are hydrogen, halogen, lower alkyl , lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, nitro or cyano ; Z is -O-, -S-, -SO-, -SO2-, -CO-, or WHEREIN R&#39;&#39;&#39;&#39; is hydrogen or lower alkyl ; and A-B is OR WHEREIN R&#39;&#39;&#39;&#39;&#39;&#39; is hydrogen or lower alkyl. These compounds possess central nervous system acting properties.

nit'e States Patent 1 Malen et al.

[ Mar. 27, 1973 [541 TRICYCLIC COMPOUNDS [75] Inventors: Charles Malen,Fresnes; Monique Desnos, Issy les Moulineaux; Jean- Claude Poignant,Wissous, all of France [73] Assignee: Societe en nom Collectii ScienceUnion et Cie, Societe Francaise de Recherche Medicale,, Suresne, France22 Filed: 111118224970 21 Appl.No.:48,498'

[30] Foreign Application Priority Data June 20, 1969 Great Britain..31,28S/69 [52] US. Cl. ..260/333, 260/239 D, 260/239 DD, 260/327 B,260/404, 260/470, 260/471 A,

[51] Int. Cl. ..C07d 87/54 [58] Field of Search ..260/333 [56]References Cited UNITED STATES PATENTS 3,546,226 12/1970 Schmutz et al...260/333 X FOREIGN PATENTS OR APPLICATIONS 283,550 1 1/1965 Australia..260/333 OTHER PUBLICATIONS Chemical Abstracts, Vol. 69 (1968) 960ldPrimary Examiner- Norma S. Milestone Att0rneyGordon W. Hueschen andTalivaldis Cepuritis [5 7] ABSTRACT Tricyclic compounds of the formula Iwherein R" is hydrogen or lower-alkyl and A-B is wherein R' is hydrogenor lower alkyl.

These compounds possess central nervous system acting properties.

6 Claims, No Drawings TRICYCLIC COMPOUNDS The present invention providestricyclic compounds of the general formula I Y l/ \JEX n is an integerof from 1 to 11 inclusive;

R is selected from the group consisting of a hydrogen atom and a loweralkyl radical containing one to five carbon atoms inclusive in a linearor branched chain;

X and Y are selected from the group consisting of a hydrogen atom, ahalogen atom selected from fluorine, chlorine and bromine atoms, a loweralkyl radical containing one to five carbon atoms inclusive in a linearor branched chain, a lower alkoxyOR, lower alkylthio SR and loweralkylsulfonyl SO R', wherein R is a lower alkyl radical containing oneto five carbon atoms inclusive, a trifluoromethyl radical, a nitroradical and a cyano radical;

Z is a bivalent radical selected from the group consisting of: O, S,SO-, SO

N-R", C II-It COand radicals wherein R" is selected from the groupconsisting of a hydrogen atom and a lower alkyl radical containing oneto five carbon atoms inclusive in a linear or branched chain; and

A-B is a bridge selected from the group consisting and CH-CH {IIIradicals wherein R is selected from the group consisting of a hydrogenatom and a lower alkyl radical containing one to five carbon atomsinclusive in a linear or branched chain.

The compounds of the general formula I wherein R represents a hydrogenatom are arnphoteric compounds which yield metal salts with bases ofalkaline or carbon atoms are basic compounds which yield salts withmineral or organic acids mentioned above. All these salts are includedin this invention.

Furthermore, some compounds of the general formula (I) exist in the formof optical isomers and of stereoisomers, which, as such, are alsoincluded in the present invention.

The compounds of the present invention are new and are prepared bycondensing a halogenated compound of the general formula Hill wherein AB, Z, X and Y have the above meanings and Hal represents a chlorine orbromine atom, with an w-amino-ester of the general formula H N (CI-ICOOR "I wherein n has the the above meaning and R represents a loweralkyl radical containing one to five carbon atoms inclusive, to give acompound of the general formula (I) wherein R represents a lower alkylradical, and hydrolyzing the resulting ester to form the correspondingcompound of the general formula (I) wherein R represents a hydrogenatom.

The condensation of the halogenated compound (II) with the w-arninoester(III) may be carried out in a suitable organic solvent, for example, analcohol, nitromethane, acetonitrile, or in an aprotic solvent, forexample, dimethylformamide, dimethylacetamide orhexamethyltriphosphoramide, at a temperature within the range from 20 to100C, in the presence of an acceptor of the hydracid formed during thereaction. This agent may be an excess of the m-aminoester (III), atertiary amine, a pyridine base, or a carbonate or bicarbonate of analkali or alkaline earth metal.

The hydrolysis of the ester formed is preferably carried out either inan acid aqueous-alcoholic medium or in an alkaline aqueous-alcoholicmedium. The decision whether to hydrolyze in an alkaline or acid mediumdepends on the stability of the heterocyclic or homocyclic centralnucleus. The acid formed may be isolated either in the form of a metalsalt, of a hydrochloride, or in the EXAMPLE 17-[8-trifluoromethyl-dibenzo (b,f) oxazepin (1,4) l lyl] aminoheptanoicacid hemihydrate Twenty-one g of methyl ortho (4-trifluoromethyl-2-amino) phenyloxybenzoate were heated under nitrogen for 7 hours at 200to 220 C, and yielded 18.6 g of crude S-trifluoromethyl-dibenzo (b, f)oxazepin (1,4)- 1 l-one, melting at 245 to 250 C.

16.4 g of this oxazepinone were added all at once, to 130 ml ofredistilled phosphorus oxychloride. Then 5 ml of dimethylaniline wereadded, the mixture was refluxed and stirred for 4 hours, then evaporateddo dryness under vacuum. The residue was dissolved in ether. The etherphase was rapidly washed with water, dried then evaporated, to yield 16g of crude 8- trifluoromethyl-ll-chloro-dibenzo (b,f) oxzepine (1,4).

Sixteen grams of freshly distilled ethyl 7-amino-heptanoate were addedall at once into a mixture of 13.7 g of8-trifluoromethy1-ll-chloro-dibenzo (b,f) oxzepine (1,4) obtained aboveand 50 ml of anhydrous nitromethane. The mixture heated up spontaneouslyto 35 to 40 C. The stirring was continued for'l hour while allowing themixture to cool down to room temperature and then kept for hours. Thesolvent was then evaporated under vacuum. The residue was taken up inchloroform and water. The chloroform layer was repeatedly washed withwater, dried and the solvent evaporated, to yield 17.5 g of ethyl 7 [8-trifluoromethyldibenzo (b, f) oxazepin (1,4) -ll-yl] aminoheptanoatewhose content of pure product determined by titration with perchloricacid in an acetic medium, was 95 percent.

Seventeen g of the ester thus obtained were added to 40 ml of N-sodiumhydroxide solution and 80 ml of ethanol. The mixture was refluxed for 30minutes and the solvent then evaporated under vacuum. The residue wastaken up in 100 ml of water and the solution extracted with ether. Theaqueous phase was acidified with 40 ml of N-hydrochloric acid. Theorganic acid precipitated in the form of an oil and was extracted withether. The ether phase was washed with water, dried and evaporated, toyield 11.8 g of 7-[8- trifluoromethyl-dibenzo (b, f) oxazepin (1,4)-1l-yl] aminoheptanoic acid hemihydrate which melted instantaneously at 90C and contained 98.5 percent of pure product. This acid could berecrystallized from benzene. This acid hemihydrate was stable in theair. The anhydrous product was hygroscopic and came back to the freeair, in the form of the hemihydrate.

EXAMPLEZ 7- [8-nitro-dibenzo (b,f) thiazepin (1,4)-11-y1] aminoheptanoicacid hydrochloride Twelve g of 8-nitro-dibenzo (b,f) thiazepin 1,4 -11'- one, melting (micro Kofler heater) at 300 to 303C with sublimation,were added to ml of phosphorus oxychloride and 3 ml of dimethyl-aniline.The mixture was refluxed and stirred for 5 hours. The product dissolvedslowly with release of hydrochloric gas. After reflux, the excess ofphosphorus oxychloride was evaporated under vacum. The residue waswashed with water and then dried in vacuum desiccator, to yield 12,2 gof 8-nitro-l l-chloro-dibenzo (b,f) thiazepine (1,4) melting at 145 to146C and after recrystallization from nitro-methane it melted at, 146 to147C (micro Kofler heater).

By utilizing the condensation method described in Example 1 there wereobtained, from 6.7 g of 8-nitrol l-chloro-dibenzo (b,f) thiazepine 1,4),8.7 g of ethyl 7- [8-nitro-dibenzo (b,f) thiazepin (1,4)-l l-yl]aminoheptanoate which, after crystallization from nitromethane, meltedat 97 to 98C.

7.4 g of the ester thus obtained were hydrolyzed with 18 ml of N-sodiumhydroxide solution and 50 ml of ethanol. The mixture was refluxed for 15minutes, then evaporated to dryness under vacuum and the residue takenup in water. The aqueous phase was acidified by adding an excess ofhydrochloric acid. The precipitated hydrochloride was suctioned off,washed with a small quantity of ice-water and recrystallized from ml ofethanol at 20 percent. Yield: 5 g of 7- [8-nitro-dibenzo (b,f) thiazepin(1,4)-1 l-yl] aminoheptanoic acid hydrochloride which meltedinstantaneously at 170C.

EXAMPLES3 to 23 The compounds whose substituents and melting points arelisted in the following Table were prepared by the process described inExamples 1 and 2 Ex. No. -AB Z n R X Y Isolated form Melting point, C.

3 N g 0 5 ll 11 (31-8 Free acid 70, instantaneous.

4 N:JJ 0 5 1[ ll (ll-7 lo 110, instantaneous. 5 t N:(|: O 5 11 C142 11Hydrochloride 190, instantaneous.

(i N J: 5 11 01-3 11 Frce acid. 110, instantaneous.

7. 0 5 11 CH 11 do 140, instantaneous.

8 0 6 ll 11 01-8 .(lo 80, instantaneous.

E). (3 ll 11 (J 113-8 .do 100, instantaneous. 10 N:(- 6 11 11 (11110-8Fn'v acid hemihydrate 100, (decomposition). 11 0 6 ll 11 (JIH S 0-1-8Fri-t acid nlonohydrate. 110, instantarnaous.

12. 13 11 ll 1 8 .do 50 (decomposition). 1a -N; f 0 n n n (iF3-7 Freeand 123.

H. NW 0 4) ll 11 (EN-8 Frvo acid hemidyln-ate" -106, instantaneous. l."iV IN 1 l) h 11 (1 (l-8 Free ncid 100 (decomposition). 111 i (l 7 ll(1'11 11 (lo 131-132.

17. N I h 'i ll 11 ll Hydrochloride 200, instantaneous.

..*. Table Continued Ex. No. A13- Z n R X Y Isolated form Melting point,C.

18 J S 5 H 01-2 H .(lo 220, instantaneous.

1'! S H H Cli'l do 160, instantaneous.

M .20 S 01 5 H 012 H Free acid 104, instantaneous.

u. 21, N S02 6 II H 01-8 d0 130, instantaneous. 22 N NH- 6 H H Cl-8 .d0.t 150 (decomposition).

23. (11 N- 6 H H Cl-S 'Sodium salt 200 (decomposition).

EXAMPLE 24 residue was recrystallized from acetonitrile. Yield: 5,2

5 0 1c acid hydrochloride, a slightly hygroscoplc product acidhydrochlonde e melting instantaneously at 134 to 136C.

Cl HNH(CH2)5COO1I N c /1\/ g EXAMPLES 25 to 28 b e l e M d l Thecompounds, whose substituents and melting C/V points are listed in thefollowing Table, were prepared by the process described in Example 24.

Ex. No. AB- Z n R X Y Isolated form Melting point 25 5 -c- 5 can. u HFreebase i oo-ioi.

26 N (]J -TJ 5 Cells H Cl-Z Hydrochloride hcmihydrate... 114-118.

27 (1 -C 6 II H H Froo acid 116-118.

28 N 74 M(HI-- ll (L lli ll (ll-.2 Hydrochloride 120, instantaneous.

A mixture of 44.6 g .of 5,6-dihydro-6,1 l-morphan- EXAMPLE 29tidine-dione 13 ml of dimethylaniline and 300 ml of dl 7-[8-methoxy-d1benzo (a,d) cyclo-heptadren-lO-yl] glsltirlleglopnl'ggslpgsrus oxychlonde was refluxed for 4 4O inohep oic acidhydrochloride The batch was then evaporated to dryness under a) vacuum,and the residue was taken up in ice-water and 6 I rapidly extracted withchloroform. The chloroform CUP 0 CH solution was washed withhydrochloric acid, then with A g n f w o 9 a water. The organic phasewas dried and evaporated I 2 1 8 under vacuum, to yield 26 g of crude6-chloro-l l-oxo- L; a 5 7 dibenzo (b,e) azepine melting at 109 to 110C. \/\b on. c 6

A solution of 19,7 g of freshly distilled ethyl 6- aminocaproate in 24ml of anhydrous nitromethane was added-to a suspension of 14.45 g ofpreviously ob- 2.4 g of sodium borohydride were added portionwise tainedcrude 6-chlOr0-l I-O -dibenz0 3) aZePine in under stirring to asuspension of 15 g of 8-methoxy- .113 o nhy nitfomethane- A slighflyexother' dibenzo (a,d) cycloheptadien-l l-one in 100 ml of mic reactionensued and the chlorinated derivative dismethanoL A strongly exothermicreaction ensued and Solved- The Whole was kept Overnight and the ketonedissolved. The whole was then refluxed for 1 evaporated to dryness undervacuum. The residue was h m k t t repeatedly taken up in water. Yield:19.6 g of a crude en ep ovemlgh and (muted wlth 200 ml of o water,extracted with chloroform, washed with water, product melting at 99 to110C .contamed dried and evaporated, to leave 13.6 g of crude productpercent of pure product, as determined with perchloric h afi acid in anacetic medium. After recrystallization from w er recrystallization fromCyclohexan? gave 150 ml of ethanol there were obtained 16.5 g of ethyl6- l 3 9 g l f (31d) cycloheptadlen'lo' [l1 oxo dibenzo (he) azepin 6 ynaminocaproate ol melting at to 86 C (micro Kofler heater). 10.5 gmelting at to 101C. 8 g of this recrystallized ester of thiscycloheptadlenol were dlssolyed in 100 ml of were added to 30 ml of2N-hydrochloric acid, and the chloroform and Saturated wlth a current oy mixture was refluxed for 30 minutes. The small quanti- 65 y 'q Aftelovernight Contact in the ty of insoluble matter, consisting of 6,1l-morphanabsence of humidity, the solvent was evaporated undertidinedione melting at about 260C was filtered off, the VaCllum, to yild 9 g of 8-methoxy-lO-chlorodibenzo filtrate was uickly evaporated todryness and the (a,d) cycloheptadiene meltin at 96 to 99C. A

specimen recrystallized from cyclo-hexane melted at thiepin-lO-ylaminoheptanoate corresponding to 80 98 to 102C (micro Kofler heater).percent of pure water.

To 9 g of this chlorinated derivative in 70 ml of gof the crude esterthus obtained were saponified nitromethane were added all at once 12.5 gof with 24.5 ml of N-sodium hydroxyde solution and 50 redistilled ethyl7-aminoheptanoate in 18.5 ml of 5 ml of ethanol, the mixture wasrefluxed for 1 hour 30 nitromethane the whole was heated for 1 hour atminutes and the ethanol was then evaporated under 60C, then the nitr mth was evaporated under vacuum. The residue was taken up in water. Theaquevacuum and th r id t k up i water h ethen ous solution was extractedwith ether, the organic layer The ether phase was decanted washed watereliminated and thfi aqueous layer was acidified N- dried and evaporated.The residue, consisting of crude hydrochloric acid to h P h Theprecipitating ethyl 7- [8-methoxy-dibenzo (a,d) cycloheptadien-IO- gummyproduct was extractfid with chloroform and the yl] aminoheptanoate whichcontained 80 percent of chloroform was dried evaporated under pureproduct vacuum. The residue was recrystallized from acetone 9.4 g of theester thus obtained were added to 100 ml alcohol Yield 5 P d1 -l lofaqueous hydrochloric acid; the whole was refluxed dlhydrodlbehzo hamlhoheptaholc for 3 hours, then evaporated to dryness under vacuum l gwhlch melted mstamaheously at and the residue was taken up in boilingacetonitrile. The residue was recrystallized from water, to yield 4.5EXAMPLES E to 37 g of d1 7 8-methoxy-dibenzo (a,d) cycloheptadien- Thecompounds, whose substituents and melting lO-yl] aminoheptanoic acidhydrochloride, melting at points are shown in the following Table, wereprepared 206 to 209C (micro Kofler heater). by the process described inExample 32 Ex. No. AB Z n R X Y Isolated form Melting point, C.

33 CH2CH S 6 H H H Free acid hemihydrate. 149-152 (mieor Keller).

34 CH1CH- S 6 II Cl8 H Hydrochloride 220, instantaneous.

35 -CH1CH S 6 11 01-8 (71-2 d0 218-220, instantaneous.

36 -CHzCH S 6 H H OCH3-2 .d0 175-176.

37 CH CH- O 6 H H Cl-2 Free acid 60 (decomposition).

EXAMPLES and 31 The new compounds of the invention and theirphysiologically tolerable salts possess valuable phar- The compounds,whose substituents and melting macological and therapeutic properties,especially actpoints are shown in the following Table, were prepared ingon the central nervous system.

by the process described in Example 29: Their toxicity is weak and theLD 50 determined in A-ll--- Z 11 It X Y lsolatwl form Melting point, (1.

ill) (lily (17H ill- 5 H H H llytll'llt'llllllltll IXU 1H],llislnntzuu-mls.

Ill (3H; 71! (ill; 11 H II [I 1111.. 2H)L512,luslzmlnnhnus.

EXAMPLE 32 the mice varies from 75 to 500 mg/kg by the intrae'to al t df00 d] 7- [2-chloro-l0,l1-dihydro-dibenzo(b,f)threpm-lO- g g mu e an mm 3to 2000 mg/kg by y] aminoheptanoic acid hydrochloride The variousactivities of the new compounds on the GB 5 central nervous system hasbeen evidenced by their in- NHz(CH2)e-COOH teraction with the analgesicor stimulant activity of the morphine, by the potentiation of thenarcosis of 0 ethanol and by their interaction with the stimulant efsfects of amphetamine.

' The compounds of the invention decrease the pain perception of ratssubmitted to electrical stimulation, the reactivity of mice and rats toexternal stimuli and the agressivity of isolated mice.

The here above related properties, as well as the weak toxicity,'enablethe use of the new compounds in therapy, especially in the treatment ofvarious central 7.9 g of 2,l0-dichloro-10,1l-dihydro-dibenzo (b,f)thiepine in ml of anhydrous nitromethane were added to 10 g of freshlydistilled ethyl 7-aminoheptanoate in 10 ml of nitromethane. The wholewas heated for one hour on a boiling water-bath, during nervous Systemdisorders and f m the Chlorinated derivative dissolvad prOgresSive- Thepresent invention provides also phannaceutical y and the batch was thenp ovemight- The Slight compositions for oral, rectal or parenteraladministrasoluble matter was filtered 01? and the Solvent tion,comprising a compound of general formula lor a evapolaled under Vacuum-The residue was taken p in physiologically tolerable salt thereof, inadmixture or ether and the organic layer was repeatedly washed withconjunction with a pharrnaceutically suitable carrier,

water, then dried and evaporated, to yield 11.5 g of such as, forexample, distilled water, glucose, lactose, crude ethyl 7-[2-chloro-10,l l-dihydro-dibenzo (b,f) talc, starch, magnesium stearateand cocoa butter.

ill

atoms, inclusive; lower alkylsulfonyl containing one to five carbonatoms, inclusive;

trifluoromethyl; nitro; and cyano; and B. physiologically tolerableaddition salts with suitable bases or acids where R is hydrogen, andwith suitable acids when R is lower alkyl containing one to five carbonatoms inclusive.

A compound of claim 1 which 15 7[8- trifluoromethyl-dibenzo (b,f)oxazepin (1,4) -1 l-yl] aminoheptanoic acid.

3. The compound in accordance with claim 1 wherein n is 5, R ishydrogen, X is hydrogen, and Y is chloro in the 8-position.

4. The compound in accordance with claim 1 where in n is 5, R ishydrogen, X is chloro in the 2-position, and Y is hydrogen.

5. The compound in accordance with claim 1 wherein n is 6, R ishydrogen, X is hydrogen, and Y is methyl in the 8-position.

6. The compound in accordance with claim 1 wherein n is 7, R ishydrogen, X is chloro in the 2-position, and Y is hydrogen.

2. A compound of claim 1 which is 7-(8-trifluoromethyl-dibenzo (b,f)oxazepin (1,4) -11-yl) aminoheptanoic acid.
 3. The compound inaccordance with claim 1 wherein n is 5, R is hydrogen, X is hydrogen,and Y is chloro in the 8-position.
 4. The compound in accordance withclaim 1 where in n is 5, R is hydrogen, X is chloro in the 2-position,and Y is hydrogen.
 5. The compound in accordance with claim 1 wherein nis 6, R is hydrogen, X is hydrogen, and Y is methyl in the 8-position.6. The compound in accordance with claim 1 wherein n is 7, R ishydrogen, X is chloro in the 2-position, and Y is hydrogen.